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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from J-check

Data source

Reference
Reference Type:
other: Autharized database
Title:
Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422)
Author:
Ministry of Economy, Trade and Industry, Japan
Year:
2009
Bibliographic source:
Data sheet (in fiscal 2009): prepared by Hazard-Data Evaluation Committee of National Institute of Technology and Evaluation based on the GLP study report obtained by Japanese Ministry of Economy

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test of test material in Rats
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
1H-Pyrrole-2,5-dione, 1,1'-(methylenedi-4,1-phenylene)bis-
Cas Number:
13676-54-5
Molecular formula:
C21H14N2O4
IUPAC Name:
1H-Pyrrole-2,5-dione, 1,1'-(methylenedi-4,1-phenylene)bis-
Details on test material:
- Name of test material (as cited in study report):1H-Pyrrole-2,5-dione, 1,1'-(methylenedi-4,1-phenylene)bis- Molecular formula (if other than submission substance):C21H14N2O4 - Molecular weight (if other than submission substance):358.35 g/mole - Substance type: Organic - Physical state: Pale yellow crystalline powder - Impurities (identity and concentrations):2. 0%

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Age at study initiation of dosing: 9 weeks old

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: 0.5 w/v% CMC-Na solution containing 0.1 w/v% Tween 80
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Test substance suspended in 0.5 w/v% CMC-Na solution containing 0.1 w/v% Tween 80 at 0, 40, 200 and 1000 mg/kg bw DIET PREPARATION - Rate of preparation of diet (frequency): - Mixing appropriate amounts with (Type of food): - Storage temperature of food: VEHICLE - Justification for use and choice of vehicle (if other than water): 0.5 w/v% CMC-Na solution containing 0.1 w/v% Tween 80 - Concentration in vehicle: 0, 40, 200 and 1000 mg/kg bw - Amount of vehicle (if gavage): - Lot/batch no. (if required): - Purity:
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Male: 42 dayFemale: 41 - 48 days (from 14 days before mating to day 4 of lactation)
Frequency of treatment:
Daily
Details on study schedule:
not specified
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Total: 1060 mg/kg/day: 7 male, 12 female 40 mg/kg/day: 12 male, 12 female200 mg/kg/day: 12 male, 12 female1000 mg/kg/day: 7 male, 12 femaleRecory group:0 mg/kg/day: 5 male, 5 female 1000 mg/kg/day: 5 male, 5 female
Control animals:
yes, concurrent vehicle
Details on study design:
not specified
Positive control:
not specified

Examinations

Parental animals: Observations and examinations:
Survival, clinical sign, body weigth, food consumption and urineanalysis and FOB were examiined.
Oestrous cyclicity (parental animals):
Estrous cyclicity, copulation and implantation were examined.
Sperm parameters (parental animals):
not specified
Litter observations:
Number of pups, number of live pups, sex ratio on days 0 and 4, clinical signs and body weight were examined.
Postmortem examinations (parental animals):
Hematology , clinical chemisrty , Oragn weight, gross pathology and histopathology were examined.
Postmortem examinations (offspring):
Gross pathology were examined.
Statistics:
not specified
Reproductive indices:
Fertility rat, gestation period, implantation index, live birth index, delivery index, parturition, or maternal behavior were examined.
Offspring viability indices:
Viability index on 0 and 4 day were examined.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs were observed in treated rats as compared to contorl.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
No effect on survival of treated rats were observed at 40, 200 and 1000 mg/kg bw as compared to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No change in body weight were observed in treated rats as compared to control.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No change in food consumption were observed in treated rats as compared to control.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No changes in hematological parameters were observed in treated male and female rats as compared to control.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No changes in clinical chemisrty were observed in treated male and female rats as compared to control.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No effect was observed in male rats as compared to control.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No changes in behavior test were observed in treated male and female rats as compared to control.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Focal necrosis of mucosa and hyperplasia of gastric pits in the glandular stomach were observed in female rat at 200 and 1000 mg/kg bw. The focal necrosis of mucosa is occasionally seen in the mucosa of the glandular stomach when the chemical compounds are administrated. Many of these induced changes have reversibility. focal necrosis of mucosa were not noted at the end of the recovery period, indicating reversibility. The hyperplasia of mucosal epithelium in the glandular stomach was considered to be a regeneration or restoration image against early epithelium disorder. The image of hyperplasia disappeared by complete repairing at the end of the recovery period.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No effect on Estrous cyclicity, copulation and inplantation were observed.
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
No effect on Reproductive performance of treated male and female rats were observed as compared to control.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
neuropathology
reproductive function (oestrous cycle)
reproductive performance
other: No effect observed
Remarks on result:
other: overall no developmental toxic effects observed

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
No Clinical signs were observed in treated pups as compared to control.
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
No effect on suvival of pups were observed as compared to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effect on body weight of pups were observed as compared to control.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross pathological changes were observed in treated pups as compared to control.
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
gross pathology
other: No effect observed
Remarks on result:
other: overall nodevelopmental toxic effects observed

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Any other information on results incl. tables

Absolute and relative organ weights in rats treated orally with test material in the combined repeated dose and reproductive/developmental toxicity screening test

Sex                      

Dose level (mg/kg)

Administration period

Recovery period

0

40

200

1000

0

1000

Male

Number of animals

5

5

5

5

5

5

Final body weight(g)

493.1 ± 35.9(7)a)

480.7 ± 33.6(12)

486.2 ± 27.2(12)

466.6 ± 28.1(7)

503.8 ± 12.5

510.0 ± 19.2

Absolute organ weight

 

 

 

 

 

 

Brain(g)

2.154 ± 0.079

2.122 ± 0.136

2.132 ± 0.061

2.064 ± 0.093

2.112 ± 0.030

2.168 ± 0.077

Thymus(mg)

359.2 ± 76.7

359.8 ± 105.9

334.0 ± 53.8

379.0 ± 39.2

368.2 ± 81.3

279.8 ± 52.8

Heart(g)

1.466 ± 0.171

1.528 ± 0.147

1.572 ± 0.156

1.648 ± 0.210

1.636 ± 0.145

1.636 ± 0.193

Liver(g)

12.088 ± 1.724

11.506 ± 0.575

12.304 ± 0.993

11.750 ± 0.792

13.082 ± 0.587

12.634 ± 0.882

Spleen(g)

0.826 ± 0.112

0.802 ± 0.087

0.756 ± 0.078

0.798 ± 0.099

0.782 ± 0.070

0.794 ± 0.145

Kidneys(g)

3.268 ± 0.364

3.172 ± 0.288

3.206 ± 0.320

3.002 ± 0.119

3.218 ± 0.133

3.376 ± 0.285

Adrenals(mg)

72.00 ± 15.34

65.94 ± 7.89

66.40 ± 7.42

66.04 ± 8.25

66.96 ± 7.48

64.50 ± 9.45

Testes(g)

3.339 ± 0.294(7)

3.440 ± 0.291(12)

3.472 ± 0.277(12)

3.554 ± 0.236(7)

3.284 ± 0.252

3.232 ± 0.631

Epididymides(g)

1.350 ± 0.085(7)

1.388 ± 0.083(12)

1.376 ± 0.082(12)

1.406 ± 0.089(7)

1.438 ± 0.121

1.340 ± 0.241

Relative organ weight

Brain(g%)

0.442 ± 0.035

0.452 ± 0.018

0.450 ± 0.032

0.444 ± 0.036

0.418 ± 0.013

0.426 ± 0.009

Thymus(mg%)

72.96 ± 11.71

76.58 ± 21.76

70.04 ± 7.72

81.10 ± 5.48

73.20 ± 16.87

54.90 ± 10.64

Heart(g%)

0.298 ± 0.026

0.328 ± 0.038

0.330 ± 0.016

0.354 ± 0.037

0.324 ± 0.034

0.320 ± 0.027

Liver(g%)

2.460 ± 0.166

2.458 ± 0.149

2.590 ± 0.155

2.520 ± 0.124

2.598 ± 0.134

2.476 ± 0.118

Spleen(g%)

0.170 ± 0.012

0.170 ± 0.019

0.160 ± 0.020

0.172 ± 0.030

0.156 ± 0.011

0.156 ± 0.025

Kidneys(g%)

0.666 ± 0.026

0.676 ± 0.048

0.678 ± 0.080

0.646 ± 0.060

0.638 ± 0.043

0.660 ± 0.042

Adrenals(mg%)

14.62 ± 2.23

14.12 ± 1.84

14.08 ± 2.48

14.18 ± 2.11

13.26 ± 1.28

12.60 ± 1.36

Testes(g%)

0.676 ± 0.030(7)

0.718 ± 0.079(12)

0.717 ± 0.075(12)

0.764 ± 0.077(7)

0.654 ± 0.039

0.634 ± 0.118

Epididymides(g%)

0.276 ± 0.022(7)

0.291 ± 0.025(12)

0.284 ± 0.019(12)

0.301 ± 0.032(7)

0.284 ± 0.024

0.262 ± 0.041

Female

Number of animals

5

5

5

5

5

5

Final body weight(g)

305.2 ± 26.7

314.4 ± 13.2

318.0 ± 22.2

314.2 ± 20.1

294.2 ± 31.1

299.0 ± 17.1

Absolute organ weight

Brain(g)

1.958 ± 0.044

1.940 ± 0.059

1.972 ± 0.052

2.008 ± 0.052

1.952 ± 0.048

1.990 ± 0.066

Thymus(mg)

223.2 ± 71.3

323.4 ± 54.4

303.6 ± 74.3

356.6 ± 46.3*

377.0 ± 111.5

335.2 ± 99.4

Heart(g)

1.028 ± 0.082

1.030 ± 0.037

1.078 ± 0.073

1.094 ± 0.070

0.912 ± 0.053

0.962 ± 0.040

Liver(g)

11.058 ± 0.861

10.332 ± 0.882

10.618 ± 0.689

10.824 ± 0.585

7.354 ± 0.986

7.922 ± 0.804

Spleen(g)

0.768 ± 0.094

0.624 ± 0.041

0.794 ± 0.063

0.902 ± 0.141

0.594 ± 0.065

0.522 ± 0.078

Kidneys(g)

2.212 ± 0.196

2.118 ± 0.151

2.386 ± 0.240

2.186 ± 0.222

1.986 ± 0.123

1.938 ± 0.075

Adrenals(mg)

81.30 ± 9.55

82.64 ± 4.70

79.46 ± 12.12

75.76 ± 16.53

77.86 ± 19.32

73.22 ± 10.90

Relative organ weight

Brain(g%)

0.646 ± 0.059

0.618 ± 0.026

0.618 ± 0.036

0.642 ± 0.039

0.668 ± 0.070

0.670 ± 0.056

Thymus(mg%)

72.96 ± 22.82

102.52 ± 13.98*

94.82 ± 18.35

113.64 ± 14.99**

127.10 ± 26.70

113.00 ± 35.65

Heart(g%)

0.336 ± 0.034

0.328 ± 0.011

0.338 ± 0.008

0.346 ± 0.009

0.314 ± 0.026

0.322 ± 0.008

Liver(g%)

3.632 ± 0.195

3.286 ± 0.249*

3.344 ± 0.180

3.444 ± 0.075

2.494 ± 0.086

2.646 ± 0.166

Spleen(g%)

0.254 ± 0.038

0.200 ± 0.014*

0.250 ± 0.020

0.286 ± 0.043

0.202 ± 0.008

0.176 ± 0.025

Kidneys(g%)

0.728 ± 0.033

0.672 ± 0.036

0.750 ± 0.043

0.694 ± 0.040

0.680 ± 0.060

0.650 ± 0.039

Adrenals(mg%)

26.70 ± 2.88

26.30 ± 1.17

25.08 ± 4.44

23.94 ± 3.94

26.52 ± 6.48

24.50 ± 3.87

a) Number of animals examied.

Values are expressed as Mean ± S.D.

Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01

Histopathological findings in rats treated orally with test material in the combined repeated dose and reproductive/developmental toxicity screening test

Sex

Organ Finding

Dose level (mg/kg)

Number of animals

Administration period

Recovery period

0

40

200

1000

0

1000

7

12

12

7

5

5

Male                          (Grade)

 Urinary bladder

<5>

<0>

<0>

<5>

<0>

<0>

Testis

<5>

<0>

<0>

<5>

<0>

<1>

Degeneration, seminiferous tubular epithelium, focal

1+

1

 

 

0

 

0

Degeneration, seminiferous tubular epithelium, diffuse

1+

0

 

 

0

 

1

Epididymis

<5>

<0>

<0>

<5>

<0>

<1>

Decrease, sperm

 

0

 

 

0

 

1

Seminal vesicle

<5>

<0>

<0>

<5>

<0>

<0>

Prostate

<5>

<0>

<0>

<5>

<0>

<0>

Cell infiltration, lymphocyte, interstitium

1+

1

 

 

2

 

 

Coagulating gland

<5>

<0>

<0>

<5>

<0>

<0>

Pituitary

<5>

<0>

<0>

<5>

<0>

<0>

Cyst, anterior lobe

1+

1

 

 

0

 

 

Cyst-like lesion, anterior lobe

1+

0

 

 

1

 

 

Thyroid

<5>

<0>

<0>

<5>

<0>

<0>

Ectopic thymic tissue

1+

0

 

 

1

 

 

Ultimobrancheal remnant

1+

1

 

 

1

 

 

Parathyroid

<5>

<0>

<0>

<5>

<0>

<0>

Adrenal

<5>

<0>

<0>

<5>

<0>

<0>

Brain

<5>

<0>

<0>

<5>

<0>

<0>

Spinal cord

<5>

<0>

<0>

<5>

<0>

<0>

Sciatic nerve

<5>

<0>

<0>

<5>

<0>

<0>

< > : Number of animals examined.

Grade; 1+ : Minimal, 2+ : Mild, 3+ : Moderate, 4+ : Severe,

Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01

Sex

Organ Finding

Dose level (mg/kg)

Number of animals

Administration period

Recovery period

Non-pregnant

0

40

200

1000

0

1000

1000

12

11

12

11

5

5

1

Female                                  (Grade)

 Heart

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Lymph node, mandibular

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Lymph node, mesenteric

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Thymus

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Cyst

1+

3

 

 

1

 

 

 

Spleen

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Prostate

<5>

<0>

<0>

<5>

<0>

<0>

 

Extramedullary hematopoiesis, erythrocytic

1+

2

 

 

2

 

 

 

Bone marrow, femur

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Trachea

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Lung (and bronchus)

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Accumulation, foam cell, alveolus

1+

1

 

 

1

 

 

 

Mineralization, arterial wall, focal

1+

1

 

 

1

 

 

 

Stomach

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Cyst, mucosa, glandular stomach

1+

0

1

0

0

0

0

 

Hyperplasia, foveola, glandular stomach

1+

0

0

1

3

0

0

 

Necrosis, mucosa, glandular stomach, focal

1+

0

0

1

3

0

0

 

Small intestine, duodenum

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Small intestine, jejunum

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Small intestine, ileum

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Large intestine, cecum

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Large intestine, colon

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Large intestine, rectum

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Liver

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Proliferation, bile duct

1+

1

 

 

0

 

 

 

Kidney

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Basophilic tubule

1+

0

 

 

1

 

 

 

Cell infiltration, inflammatory, pelvis, focal

1+

0

 

 

1

 

 

 

Cell infiltration, lymphocyte, interstitium, focal

1+

1

 

 

0

 

 

 

Fibrosis, focal

1+

1

 

 

0

 

 

 

Urinary bladder

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Ovary

<5>

<0>

<0>

<5>

<0>

<0>

<1>

Uterus

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Vagina

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Pituitary

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Cyst, Rathke's pouch

1+

0

 

 

1

 

 

 

Thyroid

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Ultimobrancheal remnant

1+

3

 

 

2

 

 

 

< > : Number of animals examined.

Grade; 1+ : Minimal, 2+ : Mild, 3+ : Moderate, 4+ : Severe,

Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01

Fertility and pregnancy data in rats treated orally with test material in the combined repeated dose and reproductive/developmental toxicity screening test

Dose level(mg/kg)

Administration period

0

40

200

1000

Number of pairs examined

12

12

12

12

Estrous cycle

4.18 ± 0.34

4.03 ± 0.09

4.00 ± 0.00

4.08 ± 0.29

Irregular estrous cycle

1/12

1/12

1/12

1/12

Number of pairs with successful mating

12

12

12

12

Mating index (%)a)

100.0

100.0

100.0

100.0

Number of pregnant females

12

12

12

12

Fertility index (%)b)

100.0

100.0

100.0

91.7

Pairing days until mating

3.0 ± 1.3

3.4 ± 1.8

2.8 ± 1.1

2.8 ± 1.1

Number of estrous stages without mating

0.0 ± 0.0

0.3 ± 0.5*

0.0 ± 0.0

0.0 ± 0.0

a) Mating index (%) = (Number of pairs with successful mating/number of pairs examined)×100

b) Fertility index (%) = (Number of pregnant animals/number of pairs with successful mating)×100

Values are expressed as Mean ± S.D.

Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01

Delivery and litter data in rats treated orally with test material in the combined repeated dose and reproductive/developmental toxicity screening test

Dose level(mg/kg)

Administration period

0

40

200

1000

Number of females examined

12

11

12

11

Number of females with live pups

12

11

12

11

Gestation index (%)a)

100.0

100.0

100.0

100.0

Gestation length (days)

22.4 ± 0.5

22.4 ± 0.5

22.3 ± 0.5

22.3 ± 0.5

Number of corpora lutea

16.3 ± 1.4

16.5 ± 1.8

17.3 ± 1.2

15.8 ± 1.9

Number of implantation sites

15.2 ± 1.4

15.2 ± 1.5

15.9 ± 1.0

14.8 ± 1.9

Implantation index (%)b)

92.94 ± 4.90

92.47 ± 5.65

91.98 ± 5.40

93.83 ± 6.46

Delivery index (%)c)

97.25 ± 3.41

94.67 ± 7.56

91.88 ± 10.99

92.85 ± 7.84

Number of pups delivered

14.8 ± 1.5

14.4 ± 1.7

14.6 ± 1.7

13.8 ± 2.6

Number of live pups on day 0

14.6 ± 1.6

14.4 ± 1.7

14.6 ± 1.7

13.6 ± 2.7

Number of live pups on day 4

14.5 ± 1.7

13.1 ± 3.1

14.5 ± 1.8

13.2 ± 2.6

Live birth index (%)d)

98.84 ± 2.72

100.00 ± 0.00

100.00 ± 0.00

98.55 ± 3.24

Viability index on day 4 (%)e)

99.31 ± 2.40

91.58 ± 19.79

99.36 ± 2.22

96.68 ± 4.03

Sex ratio of total number of offspring at birth (M/Total)

0.46(81/177)

0.50(79/158)

0.49(85/175)

0.45(68/152)

Sex ratio of total number of live

offspring at birth (M/Total)

0.46(80/175)

0.50(79/158)

0.49(85/175)

0.44(66/150)

Sex ratio of total number of live

offspring on day 4 (M/Total)

0.46(80/174)

0.51(73/144)

0.48(84/174)

0.44(64/145)

Sex ratio of total number of offspring at birth (M/Total, litter)

0.457 ± 0.112

0.505 ± 0.141

0.505 ± 0.141

0.453 ± 0.153

Sex ratio of total number of liveoffspring at birth (M/Total, litter)

0.456 ± 0.120

0.505 ± 0.141

0.484 ± 0.093

0.444 ± 0.157

Sex ratio of total number of live offspring on day 4 (M/Total, litter )

0.458 ± 0.117

0.506 ± 0.142

0.481 ± 0.094

0.444 ± 0.146

Body weight of pups (g)

on day 0 male

female

 

on day 4 male

female

6.9 ± 0.6

6.4 ± 0.5

 

10.7 ± 1.4

10.2 ± 1.3

6.6 ± 0.7

6.3 ± 0.8

 

10.4 ± 1.6

9.9 ± 1.5

6.8 ± 0.5

6.5 ± 0.6

 

10.2 ± 1.1

9.8 ± 1.1

6.8 ± 0.5

6.4 ± 0.5

 

10.7 ± 1.4

10.3 ± 1.4

a) Gestation index (%) = (Number of females with live pups/number of pregnant females)×100

b) Implantation index (%) = (Number of implantation sites/number of corpora lutea)×100

c) Delivery index (%) = (Number of pups delivered/number of implantation sites)×100

d) Live birth index (%) = (Number of live pups on day 0/number of pups delivered)×100

e) Viability index (%) = (Number of live pups on day 4/number of live pups on day 0)×100

Values are expressed as Mean±S.D.

Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01

 

 

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 1000 mg/kg/day for P and F1 generation when Crl:CD (SD) male and female rats treated with test material orally by gavage.
Executive summary:

In a Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test,Crl:CD (SD) male and female rats treated with test material in the concentration of0, 40, 200 and 1000 mg/kg/day orally by gavage in0.1 w/v% Tween 80 added 0.5 w/v% CMC-Na solution. No efect on survival, clinical signs, body weight, food consumption, behavior test, hematology, blood chemistry, urinalysis, organ weight and gross pathology were observed in treated male and female rats as compared to control. Focal necrosis of mucosa and hyperplasia of gastric pits in the glandular stomach were observed in female rat at 200 and 1000 mg/kg bw. The focal necrosis of mucosa is occasionally seen in the mucosa of the glandular stomach when the chemical compounds are administrated. Many of these induced changes have reversibility. Focal necrosis of mucosa were not noted at the end of the recovery period, indicating reversibility. The hyperplasia of mucosal epithelium in the glandular stomach was considered to be a regeneration or restoration image against early epithelium disorder. The image of hyperplasia disappeared by complete repairing at the end of the recovery period. In addition no reproductive effect such as Estrous cyclicity, copulation and implantation, Fertility rat, gestation period, implantation index, live birth index, delivery index were observed in treated rats as compared to control. No effect on viability, clinical signs, body weights, development and growth of pups and gross pathological changes were observed in treated rats as compared to control. Therefore, NOAEL was considered to be 1000 mg/kg/day for P and F1 generation whenCrl:CD (SD)male and female rats treated with test material orally by gavage.